Outcome and molecular characteristics of non-invasive encapsulated follicular variant of papillary thyroid carcinoma with oncocytic features.

PURPOSE: In 2016, non-invasive encapsulated follicular variant of papillary thyroid carcinoma (NI-EFVPTC) was renamed as noninvasive thyroid follicular neoplasm with papillary-like nuclear features (NIFTP). However, as the study cohort did not mention tumors with oncocytic features, such lesions are still labeled by some as FVPTC. It is therefore crucial to evaluate the outcome and molecular profile of oncocytic NI-EFVPTC. METHODS: A multi-institutional clinico-pathologic review was conducted to select 61 patients having oncocytic NI-EFVPTC. A detailed molecular profile was carried out in 15 patients. RESULTS: Oncocytic NI-EFVPTCs predominantly affected women in their 50s. There was no distant metastasis, lymph node metastases, or structural recurrence in the entire cohort. Among patients with ≥5 years of FU, all 33 individuals did not recur with a median FU of 10.2 years. Oncocytic NI-EFVPTC commonly had RAS (33%) mutations, a high frequency of mitochondrial DNA mutations (67%) and multiple chromosomal gains/losses (53%). No fusion genes were detected. CONCLUSIONS: Oncocytic NI-EFVPTC, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively with lobectomy alone without RAI therapy. These tumors share a similar mutational profile as NIFTP, FVPTC, and follicular neoplasm and are predominantly RAS-related. Like Hurthle cell neoplasms, they harbor a high frequency of mitochondrial DNA mutations, which contribute to the oncocytic cytomorphology. However, they lack the widespread chromosomal alterations observed in Hurthle cell carcinoma. Consideration should be given to include oncocytic NI-EFVPTCs as NIFTP in order to avoid overtreatment of these highly indolent tumors.

Should subcentimeter non-invasive encapsulated, follicular variant of papillary thyroid carcinoma be included in the noninvasive follicular thyroid neoplasm with papillary-like nuclear features category?

OBJECTIVE: In 2016, non-invasive, well-circumscribed and encapsulated, follicular variant of papillary thyroid carcinoma (NI-EFV PTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment of this indolent tumor. However, the study cohort did not include subcentimeter tumors, i.e., papillary thyroid microcarcinoma (mPTC) with NI-EFV morphology, and such lesions are still regarded and staged by most pathologists as microcarcinomas. It is therefore crucial to evaluate the clinical outcome of subcentimeter NI-EFVs. METHODS: A total of 52 patients with unifocal mPTC, NI-EFV from five tertiary hospitals who had at least one year clinical follow-up (FU) without post-operative RAI administration were included in the study. A control group of 57 invasive mPTC follicular variant was also included. RESULTS: The median tumor size was 0.44 cm (range 0.1-0.9 cm). There were no distant or lymph node metastases at diagnosis in all patients. Twenty-three patients (44%) underwent lobectomy alone, while the remaining received total thyroidectomy. No recurrence was observed in the entire cohort (n = 52) including all 38 patients with at least 2 years of FU (median FU: 6.3 years). Among 25 patients with ≥5 years of FU, none recurred with a median FU of 9.6 years (range 5.2-18.1 years). In contrast, in the control group with invasive mPTC follicular variant, there were 5 (9%) patients with nodal metastasis at presentation and 1 (2%) who displayed nodal recurrence. CONCLUSION: Papillary thyroid microcarcinoma, NI-EFV, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively without RAI therapy. Provided stringent inclusion criteria are met, classification of subcentimeter mPTC, NI-EFV as NIFTP should be considered in order to avoid overtreatment of these biologically indolent lesions.

RET mutation and increased angiogenesis in medullary thyroid carcinomas.

Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors.

Cytological features of "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" and their correlation with tumor histology.

Among thyroid papillary carcinomas (PTCs), the follicular variant is the most common and includes encapsulated forms (EFVPTCs). Noninvasive EFVPTCs have very low risk of recurrence or other adverse events and have been recently proposed to be designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP, thus eliminating the term carcinoma. This proposal is expected to significantly impact the risk of malignancy associated with the currently used diagnostic categories of thyroid cytology. In this study, we analyzed the fine needle aspiration biopsy (FNAB) cytology features of 96 histologically proven NIFTPs and determined how the main nuclear features of NIFTP correlate between cytological and histological samples. Blind review of FNAB cytology from NIFTP nodules yielded the diagnosis of "follicular neoplasm" (Bethesda category IV) in 56% of cases, "suspicious for malignancy" (category V) in 27%, "atypia of undetermined significance/follicular lesion of undetermined significance" (category III) in 15%, and "malignant" (category VI) in 2%. We found good correlation (κ=0.62) of nuclear features between histological and cytological specimens. NIFTP nuclear features (size, irregularities of contours, and chromatin clearing) were significantly different from those of benign nodules but not from those of invasive EFVPTC. Our data indicate that most of the NIFTP nodules yield an indeterminate cytological diagnosis in FNAB cytology and nuclear features found in cytology samples are reproducibly identified in corresponding histology samples. Because of the overlapping nuclear features with invasive EFVPTC, NIFTP cannot be reliably diagnosed preoperatively but should be listed in differential diagnosis of all indeterminate categories of thyroid cytology.

BRAF V600E and risk stratification of thyroid microcarcinoma: a multicenter pathological and clinical study.

Studies from single institutions have analyzed BRAF in papillary microcarcinomas, sometimes with contradictory results. Most of them have provided limited integration of histological and clinical data. To obtain a comprehensive picture of BRAF V600E-mutated microcarcinomas and to evaluate the role of BRAF testing in risk stratification we performed a retrospective multicenter analysis integrating microscopical, pathological, and clinical information. Three hundred and sixty-five samples from 300 patients treated at six medical institutions covering different geographical regions of Italy were analyzed with central review of all cases. BRAF V600E statistical analysis was conducted on 298 microcarcinomas from 264 patients after exclusion of those that did not meet the required criteria. BRAF V600E was identified in 145/298 tumors (49%) including the following subtypes: 35/37 (95%, P<0.0001) tall cell and 72/114 (64%, P<0.0001) classic; conversely 94/129 follicular variant papillary microcarcinomas (73%, P<0.0001) were BRAF wild type. BRAF V600E-mutated microcarcinomas were characterized by markedly infiltrative contours (P<0.0001) with elongated strings of neoplastic cells departing from the tumor, and by intraglandular tumor spread (P<0.0001), typically within 5 mm of the tumor border. Multivariate analysis correlated BRAF V600E with specific microscopic features (nuclear grooves, optically clear nuclei, tall cells within the tumor, and tumor fibrosis), aggressive growth pattern (infiltrative tumor border, extension into extrathyroidal tissues, and intraglandular tumor spread), higher American Thyroid Association recurrence risk group, and non-incidental tumor discovery. The following showed the strongest link to BRAF V600E: tall cell subtype, many neoplastic cells with nuclear grooves or with optically clear nuclei, infiltrative growth, intraglandular tumor spread, and a tumor discovery that was non-incidental. BRAF V600E-mutated microcarcinomas represent a distinct biological subtype. The mutation is associated with conventional clinico-pathological features considered to be adverse prognostic factors for papillary microcarcinoma, for which it could be regarded as a surrogate marker. BRAF analysis may be useful to identify tumors (BRAF wild type) that have negligible clinical risk.

Ectopic thyroid tissue in the adrenal gland: report of a case.

Foci of ectopic thyroid tissue are uncommon. Most sites of thyroid ectopia are confined to the neck region. The presence of ectopic thyroid tissue outside the migration pathway of the primitive thyroid in other locations is exceptional. Given that any disease of the thyroid gland may also affect ectopic thyroid tissue, pathologists has to recognize benign or malignant conditions that may develop in the ectopic focus. We present the case of a 32-year-old woman with ectopic thyroid parenchyma in the adrenal gland. Clinically, postoperative thyroid ultrasound echography and computed tomography scans did not reveal any thyroid tumor. The ectopic tissue was a cyst bordered by mature follicular thyroid structures and was histologically benign, without the molecular alterations associated with malignant tumors of follicular cell derivation (BRAFV600E, N-RAS, H-RAS, K-RAS). Review of the literature reveals that adrenal ectopic thyroid tissue is nearly always cystic and has distinctive pathologic features.

High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas.

CONTEXT: The homogeneous distribution of BRAF V600E in papillary thyroid carcinoma (PTC) has been called into question by recent reports. These studies claim that BRAF V600E is heterogeneous and is limited to tumor cell subsets in the majority of PTCs. OBJECTIVE: The objective of the study was to understand the allele distribution of BRAF V600E by evaluating the percentage of mutated neoplastic cells in a group of PTCs using two different highly sensitive analytical approaches: allele-specific locked nucleic acid PCR and 454 next-generation sequencing targeted to BRAF exon 15. STUDY DESIGN: BRAF V600E was investigated using allele-specific locked nucleic acid PCR on 155 consecutive samples of PTC. Mutated cases were reanalyzed by 454 next-generation sequencing and immunohistochemistry. Because the evaluation of genetic heterogeneity in tumor samples can be profoundly biased by contamination with normal cells, all mutation frequency data were normalized to the real amount of neoplastic cells within each tumor. RESULTS: Eighty-five of 155 PTCs (54.8%) were BRAF V600E mutated. The distribution of mutated neoplastic cells within the tumor was as follows: greater than 80% in 37 of 85 (43.5%), 30-80% in 39 of 85 (45.9%), and less than 30% in 9 of 85 (10.6%). In most of the PTCs with less than 80% BRAF V600E-positive neoplastic cells, the mutation was present in large neoplastic cell subpopulations. Tumors with less than 30% mutated neoplastic cells were smaller than tumors with a percentage of mutated cells greater than 80% or between 30% and 80% (P < .05). CONCLUSIONS: BRAF V600E is heterogeneously distributed in some PTCs. The large BRAF V600E neoplastic cell subpopulations found in mutated cases is consistent with the view that the BRAF V600E is acquired early during PTC development.

PEComa of the nasal cavity with worrisome histologic features and benign behavior: a case report.

OBJECTIVES: PEComas (perivascular epithelioid cell tumors) are a family of neoplastic lesions that share overlapping ultrastructure and morphological and immunohistochemical appearance and include angiomyolipoma, lymphangioleiomyomatosis, and clear cell "sugar" tumor of the lung, as well as similar tumors that occur in a variety of visceral, cutaneous, and soft tissue sites throughout the body. METHODS: A 40-year-old woman came to medical attention because of epistaxis and because of unilateral nasal obstruction of 3 months' duration. Endoscopic examination revealed a well-demarcated exophytic lesion attached to the anterior portion of the middle turbinate. RESULTS: The lesion was superficially located, and therefore amenable to complete surgical excision. Seven years after surgery, the patient is alive and well, without evidence of local recurrence or metastastic disease. Based on morphological and immunohistochemical appearance, a diagnosis of PEComa with worrisome histologic features was rendered. CONCLUSIONS: In the present study, we describe a PEComa that occurred in the nasal cavity and discuss the behavior of this entity. The importance of recognizing this disease will ensure its consideration in the differential diagnosis of tumors of the head that have similar morphological features. The histogenesis of PEComa still remains elusive, and collection of additional cases with a prolonged follow-up will be important in accurately determining the behavior of these distinctive tumors.

A case of pneumatosis cystoides intestinalis mimicking familial adenomatous polyposis.

In rare cases the diagnosis of Familial Adenomatous Polyposis (FAP) may not be simple or straightforward. We describe the case of a 54-year man in whom endoscopic and histological features of FAP led to proctocolectomy with ileoanal anastomosis. At anatomical examination, air-filled cystic formations in the submucosa and subserosa of the entire large bowel led to the diagnosis of "Pneumatosis Cystoides Intestinalis", a rare clinical condition featured by the infiltration (or the production) of gas within the intestinal wall. In this case the disease was associated with a long-lasting ingestion of acarbose; as suggested by previous reports, it is possible that gas produced by the fermentation of this unabsorbable carbohydrate penetrates the bowel wall giving origin to cystic formation and to the endoscopic appearance of several polypoid lesions in the large bowel. This report indicates that in rare occasions Pneumatosis Intestinalis can lead to a wrong diagnosis of FAP.

Synchronous association of two neuroendocrine gastroenteropancreatic tumors, an adenocarcinoma of the cecum, and a Meckel's diverticulum: a case report.

Neuroendocrine gastroenteropancreatic tumors constitute a heterogeneous group of neoplasms, with the primary tumors being located in the gastric mucosa, pancreas, and small and large intestine. The development of a second primary malignancy in patients with these tumors is a well-described phenomenon, and the reported incidence ranges from 12% to 46%. The most common site of associated noncarcinoid malignancies is the gastrointestinal tract, which involves from 30% to 60% of the tumors. We report a case of concurrent colon carcinoma and two neuroendocrine tumors of the duodenum.

Rapid on-site evaluation of transbronchial aspirates in the diagnosis of hilar and mediastinal adenopathy: a randomized trial.

BACKGROUND: Rapid on-site evaluation (ROSE) of transbronchial needle aspirates has long been used during flexible bronchoscopy, but its usefulness in the diagnosis of hilar and mediastinal adenopathy is controversial. The aim of the present study was to evaluate the extent to which ROSE can be valuable in patients undergoing transbronchial needle aspiration (TBNA) for the diagnosis of hilar and mediastinal adenopathy. METHODS: A total of 168 consecutive patients with enlarged lymph nodes were randomized to undergo TBNA with or without ROSE. The primary outcome measure of the study was the diagnostic yield of TBNA on a per-patient basis. Secondary outcome measures included the percentage of adequate specimens on a per-lymph node basis, the number of biopsy sites on a per-patient basis, and the complication rate of bronchoscopy on a per-patient basis. RESULTS: We found no significant difference between the TBNA group and the ROSE group in terms of diagnostic yield (75.3% vs 78.3%, respectively; P = .64), and percentage of adequate specimens (86.5% vs 78.4%, respectively; P = .11). The median (interquartile range) number of biopsy sites was significantly lower in the ROSE group (1 [1-2] vs 2 [1-2], respectively; P = .0005). The complication rate of bronchoscopy was significantly lower in patients undergoing on-site review (6% vs 20%; P = .01), whereas the complication rate of TBNA was similar among the study groups. CONCLUSIONS: ROSE of transbronchial aspirates from hilar and mediastinal nodes enables avoidance of additional biopsy without loss in diagnostic yield and reduces the complication rate of bronchoscopy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00915330; URL: www.clinicaltrials.gov

Papillary carcinoma of a thyroglossal duct cyst in a patient with thyroid hemiagenesis: effectiveness of conservative surgical treatment.

OBJECTIVE: To describe a case of thyroglossal duct cyst carcinoma that arose in a patient with right thyroid lobe hemiagenesis. METHODS: We present the imaging, physical examination findings, treatment, and clinical course of the study patient. RESULTS: A 35-year-old woman was evaluated for a neck mass that had been present for 6 months and was slowly growing. She reported a previous diagnosis of right hemithyroid agenesis. The patient's preoperative workup included ultrasonography of the neck and head and neck T1- and T2-weighted magnetic resonance imaging, which showed right hemithyroid agenesis and a cystic lesion in the median region of the neck below the hyoid bone. Findings from chest x-rays and thyroid function tests were normal. The patient underwent a modified Sistrunk procedure that included removal of the median portion of the hyoid bone. Histologic findings showed a 2.5-cm thyroglossal duct cyst with a 0.6-cm focus of follicular variant of papillary carcinoma with invasion of the cyst wall. Total thyroidectomy was not performed because of the absence of tumoral invasion of the parenchyma around the thyroglossal duct cyst and because the patient was at low risk for aggressive disease. Cervical ultrasonography examinations were performed 6, 12, and 24 months after treatment, and all findings were normal. Presently, the patient is symptom-free after 4 years of follow-up and has no evidence of disease. CONCLUSION: Incidentally discovered, well-differentiated thyroid cancer that is confined to a thyroglossal duct cyst in a patient at low risk for aggressive disease can be adequately treated by a modified Sistrunk procedure that includes the median portion of the hyoid bone.

Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial.

BACKGROUND: Although testing for human papillomavirus (HPV) has higher sensitivity and lower specificity than cytology alone for detecting cervical intraepithelial neoplasia (CIN), studies comparing conventional and liquid-based cytology have had conflicting results. METHODS: In the first phase of a two-phase multicenter randomized controlled trial, women aged 35-60 years in the conventional arm (n = 16,658) were screened using conventional cytology, and women in the experimental arm (n = 16,706) had liquid-based cytology and were tested for high-risk HPV types using the Hybrid Capture 2 assay. Women in the conventional arm were referred to colposcopy with atypical cells of undetermined significance (ASCUS) or higher and those in the experimental arm were referred with ASCUS or higher cytology or with a positive (> or = 1 pg/mL) HPV test. Sensitivity and positive predictive value (PPV) for detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were calculated. RESULTS: The screening methods and referral criterion applied in the experimental arm had higher sensitivity than that in the conventional arm (relative sensitivity = 1.47; 95% confidence interval [CI] = 1.03 to 2.09) but a lower PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66). With HPV testing alone at > or = 1 pg/mL and at > or = 2 pg/mL, the gain in sensitivity compared with the conventional arm remained similar (relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but PPV progressively improved (relative PPV = 0.58, 95% CI = 0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27, respectively). Referral based on liquid-based cytology alone did not increase sensitivity compared with conventional cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55) but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82). CONCLUSIONS: HPV testing alone was more sensitive than conventional cytology among women 35-60 years old. Adding liquid-based cytology improved sensitivity only marginally but increased false-positives. HPV testing using Hybrid Capture 2 with a 2 pg/mL cutoff may be more appropriate than a 1 pg/mL cutoff for primary cervical cancer screening.